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IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing

ABSTRACT: A constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer, resulting in proliferative advantages for cancer cells, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1 KO and parental cells show that IQGAP1 KO alters a specific AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1 KO cells, CI intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1 KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Stomach Cancer

SUBMITTER: Martina Samiotaki

LAB HEAD: Panagiota Kafasla

PROVIDER: PXD038314 | Pride | 2023-08-04

REPOSITORIES: Pride

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Set 2: IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing

Project description:A constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer, resulting in proliferative advantages for cancer cells, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1 KO and parental cells show that IQGAP1 KO alters a specific AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1 KO cells, CI intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1 KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer.

2023-08-04 | PXD038331 | Pride

IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing

Project description:A constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer, resulting in proliferative advantages for cancer cells, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters a specific AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer.

2023-08-04 | GSE218220 | GEO

Nuclear IQGAP1 promotes gastric cancer cell growth by altering the splicing of a cell-cycle regulon in co-operation with hnRNPM

Project description:Heterogeneous nuclear ribonucleoproteins (hnRNPs) play a decisive role in alternative splicing, regulating the cell proteome and contributing to human diseases. hnRNPs are nuclear proteins but it is still an open question where they localize in the nucleus and what determines their tethering to nuclear assemblies in response to signals. Here we report that IQGAP1, a cytosolic scaffold protein, localizes in the nucleus of gastric cancer cells acting as a tethering module for hnRNPM as well as other spliceosome components. The IQGAP1-hnRNPM interaction alters, among others, the alternative splicing of ANAPC10 and is required for the response of hnRNPM to heat-induced stress signals. Together, IQGAP1 and hnRNPM promote gastric cancer cell growth while their depletion leads to cell cycle arrest and halts tumour progression. We propose that IQGAP1 localizes in the nucleus and coordinates gastric tumour growth by recruiting, in response to stress-signals, spliceosome components that drive cell cycle progression.

2021-09-09 | GSE146283 | GEO

Proteomic analysis of whole brains from Ndufs4-/- mice treated with doxycycline

Project description:Mice with mitochondrial complex I deficiency (Ndufs4-/-) suffer from severe energy impairment primarily affecting the brain and die at P55. A small molecule screen developed by our lab using cells harboring human mitochondrial disease mutations identified antibiotics targeting mitochondrial translation as potent inhibitors of cell death under nutrient stress conditions. Doxycycline, which was identified amongst these antibiotics, was administered in the diet of Ndufs4-/- mice after weaning at P21. Mice fed with doxycycline showed improved motor function and significantly increased lifespan relative to untreated Ndufs4-/- mice. In order to investigate the molecular changes promoted by doxycycline in the brains of these mice, Ndufs4-/- doxycycline treated (DOX), Ndufs4-/- untreated (KO), and Ndufs4+/+ (WT) control mice were sacrificed at P55 and their brains harvested. Proteomic analysis revealed doxycycline treatment largely prevented the neuroimmune and inflammatory profile identified in the Ndufs4-/- mice. These findings implicate a potentially causality of these proteins in the neuronal cell death ultimately leading to the observed brain pathology.

2021-09-09 | PXD022860 | Pride

Ndufs4-knockout mouse with mitochondria complex I inhibitor treatment

Project description:Glucose hypometabolism is one of the major characteristics of Alzheimer's disease (AD). The energy deficiency in AD brain has been at least partially attributed to accelerated mitochondrial dysfunction than normal aging. In earlier publications, we have shown that small molecule mitochondrial complex I inhibitor CP2 facilitated mitochondrial regeneration and rescued mitochondrial deficiency in familial AD mice model APP-PS1. Here in this study, we investigated whether a typical mitochondrial deficiency mouse model could recapitulate molecular expression signatures of AD brain and whether CP2 was able to rescue the AD brain phenotype. Ndufs4 is one of the regulatory subunits of mitochondria complex I. Knockout of Ndufs4 resulted in complex I assembly failure and approximately half mitochondrial function loss. Ndufs4-knockout mice are viable but are short in lifespan (up to about 90 days). This model has been previously used to study Leigh syndrome, a heritable mitochondrial deficiency disease. In this dataset, we performed RNAseq on brains of CP2 treated Ndufs4-knockout mice and examined the expression changes upon CP2 treatment.

2023-12-01 | GSE242286 | GEO

NDUFS4 deficiency in female and male inguinal white fat

Project description:We compared gene expression between high fat diet (HFD)-fed Adipo-NDUFS4 knockout (KO) and WT mice in inguinal white adipose tissue (iWAT or scWAT).

2022-03-07 | GSE190645 | GEO

Metabolic Targeting of Cancer by a Ubiquinone Uncompetitive Inhibitor of Mitochondrial Complex I

Project description:SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through a yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, CI). Instead of affecting the quinone binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer.

2019-05-02 | MSV000083740 | MassIVE

PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Project description:We have identified a synthetically lethal relationship between the loss of chromatin modulator, ARID1A, and the inhibition of PLK1 kinase through a mechanism that involves mitochondrial dysfunction. Using normal gastric epithelium cell line, GES1, we performed a comparative gene expression analysis comparing the various permutations of wild type (WT) and ARID1A knockout (KO) genotypes and untreated cells or those treated with PLK1 inhibitor,Volasertib. Consistent with ARID1A's role as a chromatin modulator, there was widespread gene expression modulation observed when comparing the WT cells with the ARID1A KO cells. In particular, we noted that oxidative phosphorylation and ROS pathway genes were enriched in ARID1A KO cells compared to wild type cells. Volasertib treatment appeared to exacerbate the effects on gene expression induced by ARID1A KO. We also investigated how ARID1A KO and Volasertib treatment specifically modulated the expression of mitochondrial encoded genes using a more recent human genome build, hg38 (as opposed to hg19), that enabled the correct alignment of these mitochondrial genes. For this analysis, in addition to GES1s, we used the ovarian cancer cell line, OVCAR3. To answer the question of which genes facilitate preferential cell killing of Volasertib-treated ARID1A KO cells, using normal breast epithelial cells, MCF10A, we performed a genome-wide CRISPR screen using the Brunello library. We identified many genes whose knockout made ARID1A KO cells resistant to Volasertib, many of which were involved in mitochondrial process.

2022-07-06 | GSE193942 | GEO

Loss of COX4i1 leads to combined respiratory chain deficiency and impaired mitochondrial protein synthesis

Project description:The oxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes form supramolecular assemblies termed supercomplexes. The complexes are linked not only by their function but also by interdependence of individual complex biogenesis or maintenance. For instance, cytochrome c oxidase (cIV, COX) or cytochrome bc1 complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomeric as well as supercomplex forms. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance. However, the true nature of interdependency between cI and cIV is not fully understood yet. We used a HEK293 cellular model where the COX4 subunit was completely knocked out, serving as an ideal system to study interdependency of cI and cIV, as early phases of cIV assembly process are disrupted. Total absence of cIV was accompanied by profound deficiency of cI, documented by decrease in the levels of cI subunits and significantly reduced amount of assembled cI. Supercomplexes assembled from cI, cIII and cIV were missing in COX4 KO due to loss of cIV and decrease in cI amount. Pulse-chase metabolic labelling of mtDNA-encoded proteins uncovered a decrease in the translation of cIV and cI subunits. Moreover, partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial ribosomal proteins. In addition, complexome profiling revealed accumulation of cI assembly intermediates indicating that cI biogenesis, rather than stability, was the affected process. We propose, that impairment of mitochondrial protein synthesis caused by cIV deficiency represents one of the mechanisms which may couple biogenesis of cI and cIV.

2021-02-18 | PXD023367 | Pride

MiRNA Expression Profiling in Cisplatin Resistance Human Gastric Cancer Cell Lines and Their Parental Cell Lines

Project description:Cisplatin is the first-line agent utilized for the clinical treatment of a wide variety of solid tumors including gastric cancer. However, the intrinsic or acquired cisplatin resistance is often occurred in patients with gastric cancer and resulted in failure of cisplatin therapy. In order to investigate if miRNA involves in cisplatin resistance of human gastric cancer, we first screened and compared the expression of miRNAs between cisplatin resistant gastric cancer cell lines SGC-7901/DDP and BGC-823/DDP and their sensitive parental cells by miRNAs microarray.

2016-09-05 | GSE86195 | GEO

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